Dimethylformamide → N'-{3-[6-Chloro-7-({6-methoxy-7-[3-(4-methyl-3-oxopiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1,3-benzodioxol-4-yl]prop-2-yn-1-yl}-N,N-dimethylurea

HRID 1785138Notes

Reaction equation

HRID 1785138 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].C(NC(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 7912DiisopropylamineHCID 44190381Urea, N,N-dimethyl-N-2-propynyl- (9CI)2×HCID 688822194-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one

Product 1

HCID 68881130N'-{3-[6-Chloro-7-({6-methoxy-7-[3-(4-methyl-3-oxopiperazin-1-yl)propoxy]quinazolin-4-yl}amino)-1,3-benzodioxol-4-yl]prop-2-yn-1-yl}-N,N-dimethylureaYield 66%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

4-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (60 mg, 0.48 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (81 mg, 0.80 mmol). The reaction was stirred 6 hr then DMF (3 ml) added and reaction heated at 60° for 3 hr. A further 60 mg N,N-dimethyl-N′-prop-2-yn-1-ylurea was added and heating continued for 3 hr. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to an orange oil. This was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (164 mg, 66%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.99 (quintet, 2H), 2.54 (t, 2H), 2.66 (t, 2H), 2.81 (s, 9H), 3.00 (s, 2H), 3.28 (t, 2H), 3.93 (s, 3H), 4.10 (d, 2H), 4.20 (t, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.23 (s(broad), 1H), 7.85 (s, 1H), 8.40 (s(br), 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 624/626.

Workup

  1. customreaction
  2. temperatureheated at 60° for 3 hr
  3. temperatureheating
  4. waitcontinued for 3 hr
  5. customThe mixture was then evaporated
  6. customthe residue partitioned between water and dichloromethane
  7. customThe organic layer was separated
  8. washwashed with brine
  9. dry with materialdried over magnesium sulphate
  10. customevaporated to an orange oil
  11. customThis was purified by column chromatography on silica using
  12. temperatureincreasing concentrations of methanol in dichloromethane as eluent

Sources & evidence

ORD record
ord-846f11fc72ee4d4fa6b607c51158b70f
Source dataset
uspto-grants-2009_03
Patent number
US07504408B2

Reaction notes

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